Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated herein by reference as though set forth in full.
A variety of pulmonary diseases are associated with inflammation, including acute and chronic diseases. Pulmonary diseases that are associated with inflammation include, for example, asthma, emphysema, acute lung injury (ALI) and adult respiratory distress syndrome (ARDS). Many of the lung diseases associated with inflammation have a significant effect on productivity, quality of life and overall physical health. For example, there are approximately 200,000 cases of ARDS in the United States, which manifest following systemic or pulmonary insults. Thus, inflammatory lung disease has a major impact on health care.
The early stages of an inflammatory response involve the release of chemotactic molecules that recruit inflammatory cells to the site of inflammation. Following injury or infection, inflammation produces critical alterations in neutrophil activity that can trigger the development of ALI and ARDS. Central to the destructive capacity of neutrophils is the activation of proinflammatory signaling (i.e. the release of reactive oxygen intermediates, nitric oxide, proteases, matrix metalloproteinases, cytokines, etc.) and the suppression or delay of neutrophil programmed cell death. Neutrophils are endstage cells and undergo apoptosis upon release into the circulation. However, during inflammatory diseases, neutrophil apoptosis is suppressed (Jimmenez, M. et al. (1997) Arch. Surg. 132: 1263-1269; Taneja, R. et al (2004) Crit. Care Med. 32:1460-1469). Enhanced neutrophil survival at the site of inflammation promotes increased bactericidal activity and can also result in acute inflammatory damage. Tumor Necrosis Factor (TNF) and other proinflammatory cytokines are important regulators of neutrophil function during such inflammatory responses through activation of proinflammatory signaling and are involved in the suppression of neutrophil apoptosis (Kilpatrick, L. et al. (2002) Am. J. Physiol. Cell Physiol. 283:C48-57; Lee, A. et al. (1993) J. Leukoc. Biol. 54:282-288).
Some lung diseases associated with inflammation can be treated, for example, with anti-inflammatory agents such as corticosteroids. However, corticosteroids have disadvantages. For example, corticosteroids can cause complete immunosuppression and can also induce “wasting” syndrome, diabetes, hypertension, peptic ulcer, osteoporosis, fatty liver, cataracts and other undesirable side effects.
There exists a need for safe and effective anti-inflammatory agents that reduce the severity of lung diseases associated with inflammation. The present invention satisfies this need and provides related advantages as well.